Radiofrequency plasma biocompatibility treatment of inside surfaces

ABSTRACT

Internal polymeric surfaces of medical devices are provided that have enhanced biocompatibility properties. The internal polymeric surface presents an anti-thrombogenic, fibrinolytic or thrombolytic interface with body fluids such as blood flowing through medical device tubing during implantation for medical procedures. The biocompatibility enhancing agent is secured to the polymeric substrate by a spacer molecule which is covalently bound to the internal polymeric surface which had been subjected to radiofrequency plasma treatment with a low pressure plasma medium of water vapor, oxygen or combination of water vapor and oxygen gas.

This application is a continuation of application Ser. No. 004,998,filed Jan. 15, 1993, which is a continuation of Ser. No. 720,410, filedJun. 25, 1991, now U.S. Pat. No. 5,244,654, which is acontinuation-in-part of application Ser. No. 610,548, filed Nov. 8,1990, now U.S. Pat. No. 5,132,108.

BACKGROUND AND DESCRIPTION OF THE INVENTION

The present invention generally relates to enhancing thebiocompatibility of partially enclosed interior polymeric surfaces ofmedical devices such as tubing for catheters and the like. Moreparticularly, the invention relates to surface activation of polymericsurfaces such as lumens of medical-grade tubing by radiofrequency plasmatreatment as a step in achieving immobilization of anti-thrombogenicagents or the like onto interior polymeric surfaces. The radiofrequencyplasma medium is at a substantially low pressure and includes watervapor, oxygen or combinations thereof. When this medium is subjected toradiofrequency plasma discharge conditions, the polymeric surfaces ofthe device being treated, including partially enclosed interior surfacessuch as lumens, are activated for attachment thereto ofanti-thrombogenic agents such as heparinous materials and the like.

It is well known that many medical devices must have surfaces which areof enhanced biocompatibility. It is also well-known that, generallyspeaking, biocompatibility properties are enhanced by attempting tosecure anti-thrombogenic agents to polymeric surfaces of medicaldevices, particularly those which are blood-contacting surfaces to beimplanted or otherwise used during medical procedures and the like. Inmany instances, it is particularly undesirable to have theanti-thrombogenic agent leach away in wet environments such as areencountered by medical devices that engage blood or other body fluids.At times, these surfaces in need of biocompatibility enhancement arepartially enclosed interior surfaces such as lumens of catheters orother medical tubing.

Certain attempts have been made and approaches have been suggestedwhereby a polymeric surface is activated by treatment with a plasmawhich in turn reacts with heparin or the like to provide a polymericsurface having anti-thrombogenic properties. Included are patentsincorporating plasma discharge treatment with a gaseous environmenthaving a variety of gases, including inert gases and organic gases.Patents in this regard include U.S. Pat. Nos. 4,613,517, 4,656,083 and4,948,628, which mention a variety of plasma media including thosegenerated from hydrogen, helium, ammonia, nitrogen, oxygen, neon, argon,krypton, xenon, ethylenic monomers and other hydrocarbons,halohydrocarbons, halocarbons and silanes. It will be appreciated thatvarious ones of these plasma media are relatively expensive and can behazardous to use within a manufacturing environment and/or to dispose ofas waste. Also, certain plasma media are more suitable for treatment ofspecific substrates.

It is desirable to provide a surface treatment procedure which isavailable for use in connection with rendering anti-thrombogenic any ofa number of surfaces of medical devices or the like, including partiallyenclosed interior surfaces. It is further desirable that any plasmadeposition procedure included in this regard avoid the need to useplasma media that are expensive, potentially hazardous or otherwisedifficult to handle. At the same time, any plasma media should stronglybind the anti-thrombogenic agent to the surface being treated,preferably while also accomplishing this in an especially efficientmanner that is readily susceptible to use on a large scale.

While certain approaches have been suggested which are particularlydesigned for treating interior surfaces, these typically requirespecifically designed equipment and/or are not particularly useful fortreating interior surfaces which are spaced a relatively long distancefrom the access opening to the interior surface. This situation wouldoccur, for example, in attempting to treat a long length ofsmall-diameter tubing such as that for an angiographic or angioplastycatheter, particularly when it is important that entire length of thetubing, including the internal surface at the mid-length of the tubing,is to be treated. In addition to the patents mentioned hereinabove, thefollowing patents describe devices for treating surfaces such as theinside of a tubular body: U.S. Pat. Nos. 4,261,806, 4,692,347 and4,846,101.

It has been discovered that plasma media which include a substantialconcentration of water vapor or oxygen, either alone or in combinationwith each other, and when provided at especially low pressures, achieveespecially advantageous activation of partially enclosed interiorsurfaces such as the lumen of an elongated, small diameter tubing, whenthe low-pressure plasma medium is subjected to radiofrequency plasmatreatment conditions. The thus activated surface is preferably treatedwith a spacer component having amine moieties, particularly spacercomponents which have primary or secondary amine groups. Ananti-thrombogenic agent or the like, typically with the assistance of acoupling agent, is covalently bound to the spacer component. The resultis an evenly covered biocompatible surface that significantly avoidsleaching of the anti-thrombogenic agent or the like out of the partiallyenclosed interior surface such as the tubing lumen.

It is accordingly a general object of the present invention to providean improved method for treating interior polymeric surfaces and medicaldevices or the like having such surfaces.

Another object of this invention is to provide improved medical devicecomponents such as tubing having internal polymeric surfaces withanti-thrombogenic agents or the like immobilized thereon.

Another object of the present invention is to provide an improvedanti-thrombogenic interior polymeric surface and method of making samewhich utilizes radiofrequency plasma discharge techniques that avoid theuse of expensive or hazardous plasma media and that avoid the need forspecifically designed plasma treatment equipment.

Another object of this invention is to provide an improved method forcovalently binding anti-thrombogenic agents or the like to substantiallyenclosed polymeric surfaces, which agents do not leach away in wetenvironments, as well as to the improved substantially enclosedpolymeric surfaces thus produced.

Another object of the present invention is to provide an improvedprocess for rendering interior surfaces of medical device components,such as narrow tubing, anti-thrombogenic through a process by which themean free path of the gaseous treatment media generally approximates thedimensions of the interior volume such as the inside diameter of medicalgrade tubing, whereby the reactive Species are able to penetrate theinside volume of the device before they become deactivated in thegaseous phase.

These and other objects, features and advantages of this invention willbe clearly understood through a consideration of the following detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 demonstrates the results of Example 1.

FIG. 2 demonstrates the results of Example 2.

FIG. 3 demonstrates the results of Example 3.

FIG. 4 demonstrates the results of Example 4.

DESCRIPTION OF THE PARTICULAR EMBODIMENTS

The present invention is particularly suitable in connection with thetreatment of interior surfaces of medical device articles havinginterior surfaces which are not easily contacted, such as mid-lengthinterior surfaces of medical device tubing having an especially smallinternal diameter. Specific medical device articles which areadvantageously treated according to the invention include catheters,cannulas, angioplasty balloon catheters and the like and any otherdevices having operational requirements and properties that can beimproved by attaching an anti-thrombogenic, fibrinolytic or thrombolyticagent to one or more surfaces of the device. Typically these types ofdevices or at least the internal surfaces thereof are made of polymericmaterials. In the event that the surface to be treated in accordancewith this invention is made of some other material, a thin layer of asuitable polymeric material first can be applied to the surface to betreated.

Polymers which are suitable for use as the surface to be modified withan anti-thrombogenic agent or the like in accordance with the presentinvention include various polyurethane components such as polyurethanesand polyurethane copolymers such as Pellethane Polymers. Included arepolyurethane-polyester copolymers, polyurethane-polyether copolymers andnylon-polyether copolymers such as Vestamid. Other polymers which can betreated according to the invention include Silastic (silicon rubber),nylons and other polyamides, nylon-polyester copolymers, polyolefinssuch as high density polyethylene and the like. The selected polymermust have overall properties which, except for thrombus concerns, renderthe polymers suitable for the interior surface of a medical device madein accordance with the present invention.

In accordance with the invention, these types of interior polymericsurfaces are made more suitable for long-term or short-term contact withflowing blood or other body fluids. This is accomplished by attaching ananti-thrombogenic agent, fibrinolytic agent or thrombolytic agent to theinterior surface. These agents are used in relatively small amounts, andthey are attached in such a manner that they remain biologically active,while at the same time being affixed to the polymeric surface in sosecure a manner that the agents will not leach away in wet in vitro orin vivo environments.

Securement of the anti-thrombogenic agent or the like onto the polymericinterior surface includes positioning the tubing or the like having theinterior polymeric surface within an apparatus to provide aradiofrequency plasma discharge environment. Devices for providing suchan environment are generally known in the art. Typical devices in thisregard are shown, for example, in U.S. Pat. Nos. 4,632,842 and4,656,083, the subject matter thereof being incorporated by referencehereinto. In devices used according to this invention, a reactor chamberis provided, and the device having the internal surface to be treated issimply inserted into the chamber without requiring any specialstructures or positioning. The chamber is evacuated by a suitable vacuumpump or the like, typically to a pressure below the treatment pressuretargeted for the radiofrequency plasma discharge.

A source of fluid which provides the plasma environment is fed into theevacuated chamber, and the desired treatment pressure for the plasmamedium is maintained. Glow discharge is induced within the reactorchamber by an electrode assembly disposed about the chamber. Forexample, when the chamber is generally cylindrically shaped, theelectrode assembly can include a pair of band electrodes that aremounted on a traveling block which moves along a desired length of thereactor chamber. The electrode assembly can include instead aradiofrequency coil or the like. After the flow of treating medium orfluid has been established at the desired pressure, discharge isinitiated by generating a radiofrequency electric field within thereactor chamber, thereby inducing treatment of the interior polymericsurface. The radiofrequency electric field can be applied to the chambereither capacitively or inductively.

In accordance with the present invention, the treating fluid or plasmamedium is provided within the chamber. When the radiofrequency electricfield is applied to this plasma medium, reactive species are created.The reactive species, when they encounter the polymeric surface, reactwith atoms and/or molecules of the polymeric material, thereby modifyingthe chemical nature of the surface. It is believed that the polymericsurface is modified by causing the formation of carbon groups and/orhydroxyl groups on the surface of the polymeric material. Provided theneeded low pressure conditions are maintained, the interior polymericsurface will thus be treated.

With more particular reference to the treating fluid or plasma medium,air or other gas is first evacuated from the radiofrequency treatmentchamber until virtually no air or other gas remains therewithin. Thenthe water vapor or oxygen is pumped or otherwise injected into thechamber. It is also possible to mix the oxygen with the water and/orwater vapor, which can further enhance the efficiency of the surfacemodification carried out in accordance with this aspect of theinvention. The atmosphere within the chamber can be 100% water vapor or100% oxygen, based upon the total volume of the fluid within thechamber. When water vapor and oxygen are mixed, the mixture can have aslow as about 40% by volume of water vapor. When water vapor and oxygenare included in the plasma gas within the chamber, the preferred volumeof water vapor is between about 40 and about 90 volume percent, with thebalance being oxygen. It will be appreciated by those familiar withplasma discharge techniques that these volume percents are as presentwithin the chamber at any instant in time because these are flowingfluids.

Concerning the treating fluid or plasma medium to be maintained duringradiofrequency plasma surface modification procedures, the pressureshould not exceed about 0.25 Torr, typically less than about 0.2 Torr.Generally speaking, the plasma gas pressure will be no lower than 0.01Torr. Preferably, the treatment pressure should be maintained belowabout 0.1 Torr. At these reduced pressures, an average gaseous moleculewill travel longer before it encounters another gaseous molecule. Ingaseous kinetics, this is referred to as the mean free path. This longermean free path at reduced pressures results in increased diffusionlength of the reactive species, as well as of other species in theplasma species. If the dimension of a confined volume, such as thediameter of a tubing, is comparable to the mean free path of thereactive species, there is a much higher probability that the reactivespecies entering within the interior surface will collide with the wallof the device rather than undergo a gas phase collision. These wallcollisions cause the inside surface to be chemically functionalized asrequired by the present invention.

These specific conditions can be used to deposit thin film on the insidesurfaces using depositing monomers as plasma media. By the procedureaccording to the invention, the internal surfaces or lumens of tubingshaving an internal diameter of 0.072 inch or lower and a length of up toabout 4 feet is successfully treated. Often such tubings are used ascatheters for diagnostic and interventional purposes. For example, thetubing can have a lumen diameter of less than about 0.1 inch and have alength suitable for use as a catheter for diagnostic or interventionaluses. Generally speaking, treatment of tubing of this general size andwithin uncomplicated equipment is successfully carried out within about10 to 30 minutes within an operating pressure range of between about0.04 Torr and about 0.1 Torr.

When a polymeric surface such as Silastic (silicone rubber) is to betreated with the water vapor, oxygen or water vapor/oxygen plasma, it ispreferred to pretreat the silicone rubber surface. A suitablepretreatment is within an inert gas plasma such as argon and the like.Suitable reactive species are formed thereafter with the water vapor,oxygen or water vapor and oxygen plasma as discussed herein. Theresulting reactive species-modified polymeric surface is then treatedwith a spacer molecule which provides reactive sites for attachment ofthe anti-thrombogenic agent or the like thereto and thus to thepolymeric surface. Preferred spacer molecules are those which containprimary or secondary amine groups. Exemplary molecules having suitablespacer groups include albumin, streptokinase, urokinase,polyethyleneimine (PEI) and the like, and combinations thereof.

Covalent linkages between the reactive sites (typically carboxyl groupsor hydroxyl groups) on the functionalized polymeric surface and theamine groups of the spacer molecule are formed. Generally speaking, thecovalent linkages are accomplished by a condensation ortrans-esterification reaction therebetween, often while using a suitablecoupling agent. Typical coupling agents in this regard include1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC),dicyclohexyl carbodiimide (DCC) or other known coupling agents and thelike.

The spacer components are typically applied in solution form. Forexample, a spacer component such as polyethyleneimine can be utilizedwithin a water solution containing approximately one percent by weightof PEI. Typically, the spacer component will be present at aconcentration of between about 1.0 and about 5.0 weight percent, basedupon the weight of the spacer solution.

A suitable anti-thrombogenic, fibrinolytic or thrombolytic agent is thencovalently bound to the spacer group, also by means of condensation ortransesterification chemistry. It is preferred that the agent exhibitacid functionality, whereby the carboxyl groups form a covalent linkagewith amine groups of the spacer component. The resultant device has ananti-thrombogenic internal surface from which the anti-thrombogenicagent does not readily leach.

Exemplary anti-thrombogenic agents include heparinous components such asheparin, hirudin, heparin-albumin conjugates, hyaluronic acid, and thelike. Illustrative fibrinolytic or thrombolytic agents includestreptokinase, urokinase, and the like. Combinations of spacer componentand of anti-thrombogenic agent or the anti-thrombogenic agent by itselfcan be used in the anti-thrombogenic agent composition which is attachedto the modified polymeric surface having reactive sites. Theanti-thrombogenic agent or the like is applied in the form of a solutionhaving between about 10 and about 20 weight percent ofanti-thrombogenic, fibrinolytic or thrombolytic agent, based upon thetotal weight of the composition.

The following examples illustrate the process and product, as well asperformance results.

EXAMPLE 1

Nylon 12 tubing having an inner diameter of 0.055 inch and a length of39 inches was treated in a tubular radiofrequency plasma reactor. Theplasma was created in the tubular chamber by capacitively coupling theRF atone end of the tubular reactor so that the visible part of theplasma was confined to one end of the tubing. Oxygen was the plasmamedium. It was present at a pressure of 0.07 Torr, and the treatmentproceeded for 15 minutes at 20 watts of power. A pressure regulator waspresent at the downstream portion of the device in order to control theflow of gases and to maintain the desired plasma gas pressure within thereactor. Treatment was effective without requiring any specificorientation of the tubing being treated within the reactor. Aftertreatment was completed, the treated tubing was removed from the reactorand tested to determine the extent of treatment throughout the lumenthereof. The 39 inch tubing was cut into 25 tubing pieces, each 4 cm inlength. Each length was numbered 1 through 25 starting from one end tothe other. Each piece was dipped into a beaker of de-ionized water. Theheight to which water moved within the lumen of each piece indicated theextent of surface functionalization that enhanced capillary rise whencompared with a surface such as one that had not been subjected to anytreatment. Thus, each piece of the tubing was able to support a columnof water whose height was a function of the surface energy of the insidesurface and thus an indication of the degree to which the inside surfacehad been functionalized by the radiofrequency plasma.

FIG. 1 plots the capillary rise for each 4 cm length of tubing, the plotbeing in order along the length of tubing prior to severance and at thetime of its treatment. It will be appreciated that FIG. 1 indicatesthere was a gradient of treatment effect from the ends to the center ofthe tubing. The treatment of even the central-most 4 cm lengths wasfound to be adequate to attach an anti-thrombogenic agent to the lumenthereof.

EXAMPLE 2

The procedure of Example 1 was substantially repeated at differentvarious operating pressures and under the same one-end plasmaarrangement under 20 watts of power. FIG. 2 is a plot which indicatesthe effect of operating pressure for constant treatment time, plottingcapillary rise versus position along the length of tubing prior toseverance. The areas which received minimal treatment were at and nearthe midpoint along the length of the tubing. It will be appreciated fromthese data that, as the pressure of operation is reduced, the gradientbecomes smaller indicating that the treatment length becomes longer. Thecentral areas which received minimal treatment were more extensive orlonger at the higher pressures than at the lower pressures, as can beseen in FIG. 2. The control plot is of a totally untreated Nylon 12 tubewhich was subjected to the capillary test.

EXAMPLE 3

Tests were conducted as described in Example 1, this time varying theoperating pressure. The change of treatment length as a function ofoperating pressure data are reported in FIG. 3. In this Figure, thelength of the treated tubing at which the capillary rise is 3 mm abovethe control value is plotted as a function of the operating pressure fordifferent treatment times. The control sample had a capillary rise valueof 10.3±0.3 mm. The power applied was constant, and three differenttreatment times were utilized, as reported in FIG. 3.

EXAMPLE 4

Tubing as described in Example 1 was subjected to radiofrequency plasmadeposition from an oxygen medium. The treatment was carried out within acommercial reactor, a Model 7104 unit of Branson International PlasmaCorporation. This commercial equipment included seven trays, and thetubing was laid upon the trays for treatment according to the invention.The control sample had a capillary rise value of 10.3±0.3 mm. Thetreatment pressure in the radiofrequency reactor was about 230milliTorr. The thus modified tubing was then treated with a spacermolecule, followed by attachment of heparin. Thereafter, the surface ofthe tubing, both inside and outside, was stained with toluidine blue dyeto check for the presence of heparin. The dye turned purple indicatingthe presence of heparin. The heparinized surface was extracted inphosphate buffered saline for at least 72 hours to determine whether ornot it was bound to the surface. After 72 hours in the phosphatebuffered saline, when the heparinized surface was stained with toluidineblue, the change of dye color to purple indicated that heparin was stillpresent on the surface. The presence of heparin was also confirmed byanother independent surface analytic technique, namely static secondaryion mass spectroscopy. This illustrates that the bound heparin wasimmobilized on the surface. The heparinized surface possessed a highsurface energy due to the various hydrophilic functional groups inheparin molecule. This was evident in the capillary rise measurements ofthe heparinized tubing. FIG. 4 plots the capillary rise data for theradiofrequency plasma treated sample, as well as for the heparinizedsample and the extracted sample. A flat capillary rise profile isevident for the heparinized sample, which indicates that adequateheparin is present even along the middle length of the tubing's lumen.The relatively flat profile for the extracted sample indicates that theheparin was not extracted to any substantial degree.

EXAMPLE 5

Tubing for use as catheters for diagnostic and interventional purposeswas treated as described in Example 1, except for the followingdifferences. The tubing was a nylon-polyester copolymer (Vestamid). Theplasma medium was a mixture of water and oxygen at a pressure of 0.090Torr. The treated surface was heparinized, both on the outside and inthe lumen. Positive test results indicated the immobilization of heparinon both surfaces.

EXAMPLE 6

High density polyethylene tubing having an internal diameter of 0.051inch and a length of 12 inches was treated in a water vapor plasma for10 minutes at a pressure of 0.1 Torr and under 20 watts ofradiofrequency power. The thus treated tubing was treated both on theoutside and within the lumen with heparin. Both surfaces were thentested for the presence of heparin as described in Example 4, the testspositively indicating the presence of heparin.

EXAMPLE 7

Tubing of the type described in Example 6 was treated in aradiofrequency plasma containing a medium of a mixture of water andoxygen at a pressure of 0.1 Torr. The power supply was set at 20 watts.Heparinization followed, and the heparinized surfaces were tested,thereby indicating the presence of immobilized heparin within the lumenas well as on the outside surface of the tubing.

EXAMPLE 8

Nylon 12 tubing having the size specified in Example i was treated inradiofrequency plasma using the same process conditions as in Example 1.In this Example 8, the two ends of the tubing were looped into 360degree loops and into an ellipsoidal shape. The treated samples weretested in accordance with the capillary rise techniques discussedhereinabove. The results were comparable to those for straight elongatedtubing, thereby indicating that the ends of the tubing need not bestraight for the treatment to be effective within the lumen, providedthe low pressure processing according to the present invention isachieved. In fact the treatment effects in the looped and shaped sampleswere as good as that in straight tubing. This is important in view ofthe need to treat lumens of catheters which have shapes other thanstraight tubings. Often catheters have curved portions, especially attheir end tip portions.

It will be understood that the embodiments of the present inventionwhich have been described are illustrative of some of the applicationsof the principles of the present invention. Numerous modifications maybe made by those skilled in the art without departing from the truespirit and scope of the invention.

I claim:
 1. A method for enhancing the biocompatibility of interiorpolymeric surfaces of medical device components, comprising the stepsof:positioning a medical device component within a radiofrequency plasmadischarge apparatus, the medical device component being catheter tubingwith a polymeric surface interior lumen having a diameter of less thanabout 0.1 inch, said catheter tubing having a length suitable for use asa catheter in humans; providing a reduced pressure environment withinthe radiofrequency plasma discharge apparatus, said reduced pressureenvironment being about 0.25 Torr or less; inserting into said reducedpressure environment a plasma medium selected from the group consistingof water vapor, oxygen gas, and mixtures thereof, said plasma mediumhaving a pressure of less than about 0.2 Torr; subjecting said plasmamedium to a radiofrequency electric field to induce a gas discharge inorder to form reactive species from said plasma medium within the plasmadischarge apparatus and within the lumen to form a modified interiorpolymeric lumen surface comprising reactive sites which had beenmodified by the subjecting step, said subjecting step being carried outfor at least about 10 minutes and while said plasma medium has apressure of less than about 0.2 Torr; treating said modified interiorpolymeric lumen surface with a spacer component having amine groupswhereby covalent linkages are formed between the spacer component aminegroups and the reactive sites of the modified interior polymeric lumensurface to form a spacer component-treated modified polymeric lumensurface; and covalently bonding an anti-thrombogenic, fibrinolytic orthrombolytic agent having acid functionality and biologically activeproperties to said spacer component-treated modified polymeric lumensurface, whereby said modified polymeric lumen surface is rendered intoa biocompatible surface, and the anti-thrombogenic, fibrinolytic orthrombolytic agent of the biocompatible surface is resistant toextraction under in vivo conditions while retaining its biologicallyactive properties.
 2. The method in accordance with claim 1, whereinsaid plasma medium includes between about 40 to about 90 volume percentwater vapor and between about 10 and about 60 volume percent oxygen,based upon the total volume of the plasma medium.
 3. The method inaccordance with claim 1, wherein said treating step utilizes a spacercomponent selected from the group consisting of primary amines,secondary amines, and mixtures thereof.
 4. The method in accordance withclaim 1, wherein said interior polymeric lumen surface modified by saidsubjecting step includes reactive sites of carboxyl groups, hydroxylgroups or mixtures thereof.
 5. The method in accordance with claim 1,wherein said treating step is carried out in the presence of a couplingagent.
 6. The method in accordance with claim 1, wherein said contactingstep contacts said spacer component-treated modified polymeric surfacewith a heparinous material.
 7. The method in accordance with claim 1,wherein said subjecting step is carried out while said plasma medium hasa pressure of less than about 0.1 Torr.
 8. The method in accordance withclaim 1, wherein the catheter tubing in said positioning step has alumen diameter of about 0.072 inch or less.
 9. A medical devicecomponent having a biocompatible polymeric surface, wherein said medicaldevice component is catheter tubing, said catheter tubing having a lumenwith a diameter of less than about 0.1 inch and having a length suitablefor use as a catheter in humans, and said biocompatible polymericsurface comprises an interior polymeric lumen surface which has beenmodified by subjecting the interior polymeric lumen surface toradiofrequency discharge treatment within a low-pressure plasma mediumfor at least about 10 minutes to provide a treated interior polymericlumen surface, the plasma medium selected from the group consisting ofwater vapor, oxygen gas, and mixtures thereof, said plasma medium havinga pressure of less than about 0.2 Torr, followed by treatment of thetreated interior polymeric lumen surface with a spacer component havingamine groups forming covalent linkages with the treated interiorpolymeric lumen surface to form a spacer component-treated interiorpolymeric lumen surface, after which an anti-thrombogenic, fibrinolyticor thrombolytic agent having acid functionality has been covalentlybonded to the spacer component-treated interior polymeric lumen surfaceto provide a biocompatible partially enclosed interior polymeric lumensurface.
 10. The medical device component in accordance with claim 9,said polymeric surface is a polyurethane, a polyurethane copolymer, anylon, a polyamide or a silicone rubber polymer.
 11. The medical devicecomponent in accordance with claim 9, wherein the medical devicecomponent is a component of a catheter, a cannula or a balloon catheter.12. The medical device component in accordance with claim 9, whereinsaid covalent linkages between the modified polymeric lumen surface andthe spacer component are between carboxyl or hydroxyl groups formed bythe radiofrequency discharge treatment on the polymeric surface andprimary or secondary amine groups of the spacer component.
 13. Themedical device component in accordance with claim 12, wherein a covalentlinkage is present between primary or second amine groups of spacercomponent molecules and the acid functionality groups of theanti-thrombogenic, fibrinolytic or thrombolytic agent.
 14. The medicaldevice component in accordance with claim 9, wherein said diameter ofthe catheter tubing lumen is about 0.072 inch or less.
 15. The medicaldevice in accordance with claim 9, wherein said plasma medium has apressure of less than about 0.1 Torr.